THE CA2-SENSING RECEPTOR GENE (PCAR1) MUTATION T151M IN ISOLATED AUTOSOMAL-DOMINANT HYPOPARATHYROIDISM()

Isolated autosomal dominant hypoparathyroidism is a heterogeneous diso rder characterized by parathyroid hormone (PTH) deficiency, hypocalcem ia and hyperphosphatemia. The candidate gene approach was used to stud y a large Norwegian family. The loci for the PTH gene, PTH receptor ge ne and RET protooncogene were excluded using dinucleotide markers and restriction fragment length polymorphism analysis. Complete cosegregat ion of this trait was found with the chromosomal region 3q13, using th e short tandem repeat markers D3S1267, D3S1269, D3S1303, D3S1518, and RHO. This region contains the candidate locus for the Ca2+-sensing rec eptor (PCAR1). By single-strand conformation polymorphism (SSCP) analy sis of all PCAR1 exons followed by automated sequencing, we identified a C to T transition in exon 2 (cDNA position 452) on the mutant allel e in the family. The mutation predicts a substitution of Thr to Met in amino acid position 151 (T151M). A StyI restriction site created by t he nucleotide substitution was used to confirm the mutation on all all eles, as well as to exclude it among 100 normal alleles (blood donors) . SSCP analysis also identified a novel polymorphism of PCAR1 intron 4 (1609-88t-->c) on normal alleles. The T151M mutation is located in th e extracellular N-terminal domain of PCAR1, which belongs to the super family of G protein-coupled receptors. We suggest that this is a gain- of-function mutation that increases the sensitivity of the receptor to [Ca2+], thereby decreasing the calcium set point.